Both the incidence and prevalence of Parkinson's disease (PD) increase steeply with aging, affecting approximately 7 per 1,000 individuals aged 40 years and over, and 3 per 100 subjects aged 80 years and over. The causes of this disabling disease are unknown. The long term goal of this research is to clarify the existing controversy on the role of genetic versus environmental factors in the etiology of PD. The study will investigate the risk of PD associated with a family history of PD, Alzheimer's disease, essential tremor, amyotrophic lateral sclerosis, Or depression, and with a personal history of depression, head trauma, occupational toxic exposures, and smoking. In addition, we will study the genetic segregation of PD and other associated disorders within families and the interaction between genetic and environmental factors. The study design consists of a case-control study of PD in a population-based sample and a genetic study of PD in a population-based sample augmented by referral patients. The case-control study will include all incident cases of PD occurring in Olmsted County between 1976 and 1995 and identified through the Rochester Epidemiology Project records-linkage system (expected N = 200). A population control free of PD or other parkinsonism will be matched to each case by age and gender. For both cases and controls, we will collect information regarding personal history and family history using a telephone interview and the abstracting of inpatient and outpatient medical records included in the records-linkage system. First-degree relatives of cases and controls (expected N = 3,600) will be interviewed via telephone, eligible relatives will be examined directly, and/or will have their medical records abstracted. Analyses will be based on case- control comparisons and on the comparison of cumulative incidence curves of PD and other study diseases in relatives. This study is strong because it includes all incident cases of PD from a defined population; it uses representative population controls; data collection is obtained from multiple sources and is partly based on historical data; and the disease status of relatives is confirmed through neurologic examination and/or medical records. This study can be conducted efficiently in the population of Olmsted County where a records-linkage system has been in place for more than half a century. The genetic study will include the 200 population-based cases mentioned above, 200 cases referred from a 120-mile radius around the Mayo Clinic, and 200 cases referred from a 5-state region (total N = 600). These cases, their spouses (expected N = 480), and their first-degree relatives (expected N = 5,400) will be interviewed via telephone and directly examined whenever eligible. We will assess whether familial clustering of PD can be explained by a single major gene using complex segregation analyses. in addition, we will compare the pattern of genetic clustering in the population-based sample with the two referral samples to address possible referral bias. These studies will contribute greatly to understanding the causes and possible prevention of PD.